By: Aya Alrmah
Photo Credit: The Defeating Epilepsy Foundation
This article is meant for educational purposes only and should not be taken as direct medical advice. For any questions or concerns, please speak to your healthcare provider.
Introduction
Valproic acid (VPA), a natural fatty acid found in plants and animals, has been used as an anticonvulsant since the late 1970’s (Rahman et al., 2024). There are different compounds containing VPA, such as divalproex sodium and valproate sodium. They are absorbed in different ways by the body, and ultimately are converted to VPA, which is the desired therapeutic agent (American Society of Health-System Pharmacists, Inc., 2019). The FDA has officially approved VPA to be used independently or in combination with other drugs in the treatment of complex partial seizures (Rahman et al., 2024), the most common type of seizure, where the patient may appear to be daydreaming or unaware of their surroundings (Cedars-Sinai Health Library, n.d). It has been used for other types of seizures as well, such as simple and complex seizures. VPA is relatively affordable and has been a life changing medication for many people all over the world (Collins-Yoder & Lowell, 2017).
Who is it for and how is it administered?
VPA has significantly reduced the amount of seizures a patient may experience, but like all antiepileptic drugs, it is not a cure for epilepsy. It has been used to treat multiple forms of seizures in both adults and pediatric patients under the age of 10. VPA has also shown great results in treating certain symptoms of bipolar disorder, a condition that causes extreme change in mood, from episodes of severe depression to manic highs. It has also been used in the prevention of migraines, but does not provide relief if they have already started (Rahman et al., 2024).
VPA can be taken orally and can be prescribed as a delayed-release tablet, which means the tablet will be absorbed in the small intestine after it passes through the stomach. This is done to prevent any stomach irritation. The dosage strength may come as 125mg, 250mg or 500mg. The prescribed dose will depend on multiple factors that your doctor or pharmacist will consider.
Another dosage form is the extended-release tablet, where VPA is slowly released into the body, supplying it with a steady stream of VPA. The extended-release tablet strengths come at 250mg or 500mg. Both may be taken with food to prevent stomach upset, but it is not mandatory. Other dosage forms include sprinkle tablets, which are small beads filled with medication that can be sprinkled over food and swallowed. The tablets should not be chewed unless otherwise specified by your doctor. VPA can also come in the form of a syrup, which should not be mixed with any other beverages unless told otherwise by your healthcare provider. The typical dose is multiple times a day except for the extended-release tablet, which is taken once daily (American Society of Health-System Pharmacists, Inc, 2019).
How does it work?
The mechanisms of action for VPA are numerous, and the specifics aren’t entirely known. However, there are some strong ideas on how it may work. The first mechanism is its ability to inhibit voltage gated sodium channels. How and why is this important? Think of voltage gated sodium channels as traffic lights in a busy intersection. These traffic lights (the voltage gated sodium channels) control when cars (sodium ions) are able to enter the intersection (cell). When the traffic light is red, no cars enter the intersection, if the traffic light is constantly green this will cause the jamming of the intersection. The same idea can be used when talking about these voltage gated channels. Epilepsy causes the “green light” to be turned on more frequently which leads to increased amounts of neuronal activity, one of the main causes of seizures. VPA helps reduce the amount of time the “green lights” are turned on, thus allowing the intersection (neuron) to work normally. It also helps regulate another type of gate found on the cell called the calcium channel. This channel is responsible for many functions such as neuronal signaling, gene expression and neurotransmitter release.
Another key mechanism of VPA is that it enhances the synthesis of an important inhibitory neurotransmitter known as gamma-aminobutyric acid (GABA). VPA influences this natural process by increasing the activity of glutamic acid decarboxylase (GAD), which is one of the factors responsible for creating GABA. As mentioned earlier, seizures are a result of increased electrical impulses in the brain, so one of the ways to combat that is by reducing this extra energy. By increasing GABA’s concentration, it leads to a more inhibitory action. VPA also increases GABA concentration by inhibiting its metabolism; this is done by stopping the function of the enzyme responsible for GABA’s breakdown (Rahman et al., 2024).
We now understand how VPA affects our body, but how does our body interact with VPA? This is known as the pharmacokinetics of the drug, how the body absorbs, distributes, metabolizes and gets rid of the medicine.
VPA has relatively good oral absorption, where approximately 80% of the ingested drug is absorbed into the bloodstream.
After it gets absorbed, VPA gets distributed to the target areas of the body through the blood. VPA has a high affinity to a plasma protein found in the blood, this causes around 90% of the absorbed VPA to bind with albumin, the favored plasma protein. Due to its preference to stay bound to albumin, VPA concentrations are highest where albumin is found. VPA is rarely found in tissue due to this bond with albumin. However, it is able to travel across a web of small blood vessels known as the blood-brain barrier. This network connects the brain with a blood supply, and certain compounds are able to pass through and into the cerebrospinal fluid (CSF), VPA being one of them. As approximately 10% to 20% of the plasma concentration of VPA reaches the CSF, the liquid found in the central nervous system, it starts to exert its anticonvulsant effect.
After the body has used up the VPA, it must break it down so it can be excreted. This process is known as the metabolism of the drug and is heavily done in the liver. This creates certain metabolites (breakdown products) that either have additional anticonvulsant properties or may be toxic and inactive.
These metabolites then travel to the kidney where they are primarily excreted through the urine (Rahman et al., 2024).
Who is VPA not for and what are the possible side effects?
As mentioned earlier, VPA has a strong affinity towards albumin and will bind to it majority of the time. This can lead to certain undesirable outcomes, especially when the patient is pregnant or breastfeeding. The VPA-albumin complex can cross the placenta and directly to the fetus, leading to around 70% to 100% of the maternal plasma concentration of VPA to be absorbed by the fetus. This can cause severe implications, such as serious birth defects that directly target the fetal central nervous system, leading to many physical, emotional, behavioral and psychological problems later on in life. Another unwanted place this complex can be found is the breast milk due to albumin being one of the key proteins that make it up (Rahman et al., 2024).
VPA should not be taken if the patient has any conditions that affect the brain, muscles, nerves or liver such as Alpers Huttenlocher Syndrome, urea cycle disorder, or liver disease (American Society of Health-System Pharmacists, Inc., 2019).
Possible side effects are more common in the first 6 months of treatment, or in patients under the age of 2 that are taking other medications, or have inherited conditions that may be affected by VPA. Side effects include issues that target the liver, blood or nervous system. If any abnormal symptoms appear it’s best to contact your doctor immediately.
It may also cause damage to the pancreas which is characterized by abdominal pain in the stomach and back area, vomiting or loss of appetite (American Society of Health-System Pharmacists, Inc., 2019).
What may negatively interact with VPA?
Certain drugs will induce enzymes that potentiate the breakdown of VPA, leading to its ineffectiveness. These drugs include carbamazepine, phenytoin, and rifampin. Other drugs such as aspirin, felbamate, and some nonsteroidal anti-inflammatory drugs (NSAIDs) will have the opposite effect, and block the enzymes that break down VPA, leading to concentrations higher than intended. This may lead to serious implications and toxicity. Drugs that also have high binding affinity to albumin might compete with VPA, increasing the concentration of unbound VPA that may travel to unwanted sites in the body, leading to toxicity and ineffectiveness. These are a few main examples of the drugs that need extra caution and monitoring if ever taken together. It is also highly advisable to stop alcohol intake when using VPA and other medications (Rahman et al., 2024).
Conclusion
VPA has been used for nearly half a century and has allowed many people to manage their symptoms. This drug has proven to be an effective solution in minimizing the effects of epilepsy and other conditions. By depressing voltage gated ion channels, increasing the synthesis of the neurotransmitter GABA, and by inhibiting its metabolism, VPA has proven to be a relatively safe and effective option for people all over the world. However, it should be taken with caution, and is not recommended during pregnancy as it may cause fetal deformations.
References:
American Society of Health-System Pharmacists, Inc. (2019, April 15). Valproic acid. MedlinePlus. https://medlineplus.gov/druginfo/meds/a682412.html
Collins-Yoder, A., & Lowell, J. (2017). Valproic acid: Special considerations and targeted monitoring. Journal of Neuroscience Nursing, 49(1), 56–61. https://doi.org/10.1097/JNN.0000000000000259
Complex Partial Seizures. (n.d.). In Cedars-Sinai Health Library. https://www.cedars-sinai.org/health-library/diseases-and-conditions/c/complex-partial-seizures.html
Rahman, M., Awosika, A. O., & Nguyen, H. (2024, March 19). Valproic Acid. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK559112/#:~:text=Valproic%20acid%20(VPA)%20was%20initially,in%20both%20plants%20and%20animals
